Preventives or remedies for endometriosis or uterine myoma

ABSTRACT

A drug effective for prevention and therapy of endometriosis and hysteromyoma is disclosed. The drug for prevention and/or therapy of endometriosis and/or hysteromyoma according to the present invention comprises as an effective ingredient a macrolide antibiotic.

This application is the national phase under 35 U.S.C. § 371 of PCTInternational Application No. PCT/JP01/09972 which has an Internationalfiling date of Nov. 15, 2001, which designated the United States ofAmerica.

TECHNICAL FIELD

The present invention relates to a drug for prevention and/or therapy ofendometriosis and/or hysteromyoma.

BACKGROUND ART

Endometriosis is a disease wherein endometrium or endometrium-liketissue ectopically proliferates at a site other than the inner surfaceof the cavity of uterus which is the natural site thereof. The cause ofendometriosis is unknown, and therapies such as separation of theadhered tissues by surgery, administration of hormones andadministration of analgesics are performed. However, these therapies aresymptomatic treatments, and no complete therapy exists.

Hysteromyoma is benign tumor formed on the muscle of uterus, and maycause emmeniopathy and metrorrhagia. If the myoma is large, itcompresses ambient organs, so that congestion in the pelvis, lumbago ordragging pain likely to occur. There is no therapy of hysteromyoma otherthan surgery, and the surgery is total extirpation of uterus inprinciple. Pharmacotherapy of hysteromyoma is not performed.

DISCLOSURE OF THE INVENTION

An object of the present invention is to provide a drug effective forprevention and/or therapy of endometriosis and/or hysteromyoma.

The present inventors intensively studied to discover that macrolideantibiotics are effective for prevention and/or therapy of endometriosisand/or hysteromyoma, thereby completing the present invention.

That is, the present invention provides a drug for prevention and/ortherapy of endometriosis and/or hysteromyoma, comprising a macrolideantibiotic as an effective ingredient. The present invention alsoprovides a use of a macrolide antibiotic for the production of a drugfor prevention and/or therapy of endometriosis and/or hysteromyoma. Thepresent invention further provides a method for prevention and/ortherapy of endometriosis and/or hysteromyoma, comprising administering amacrolide antibiotic to a patient suffering from endometriosis and/orhysteromyoma, in an amount effective for the prevention and/or therapyof endometriosis and/or hysteromyoma.

By the present invention, a drug effective for prevention and therapy ofendometriosis, which can cure endometriosis was first provided. Thenumber of patients suffering from endometriosis is now rapidlyincreasing, and endometriosis is now one of the main causes ofmenorrhalgia and infertility. Thus, the present invention is thought togreatly contribute in the field of therapy of infertility, and therapyand prevention of menorrhalgia. Further, macrolide antibiotics areeffective for prevention and therapy of hysteromyoma of whichpathological symptoms are similar to those of endometriosis.

BEST MODE FOR CARRYING OUT THE INVENTION

As mentioned above, the drug for prevention or therapy of endometriosisaccording to the present invention is effective for both prevention andtherapy of endometriosis, and comprises a macrolide antibiotic as aneffective ingredient.

Macrolide antibiotics means a group of antibiotics having lactone rings(12- to 16-membered lactone ring (the number of atoms constituting thering is 12 to 16), and having (a) neutral or (an) amino sugar(s).Examples of the macrolide antibiotics which may be employed in thepresent invention include clarithromycin, roxithromycin, azithromycin,erythromycin, josamycin, leucomycins, spiramycins, carbomycins, tylosin,angolamycin, kitasamycin, acetylspiramycin, midecamycin, oleandomycin,mirosamycin and maridomycin, as well as hydrates, non-toxic salts andderivatives thereof, although not restricted thereto. The term“derivative” herein means those compounds having the same basal skeletonas the original compound, but the substituents attached to the lactonering and/or sugar(s) are changed, and such derivatives may be used aslong as they have antibiotic properties. Examples of the non-toxic saltinclude hydrochloric acid salt, sulfuric acid salt, tartaric acid saltand citric acid salt, although the non-toxic salts are not restrictedthereto. As the macrolide antibiotic, those having 14-membered or15-membered lactone ring are preferred, and those in which two sugarunits are bound are preferred. Especially, clarithromycin, roxithromycinand azithromycin are preferred.

The drug for prevention and/or therapy of endometriosis according to thepresent invention may be administered by oral administration orparenteral administration such as intravenous, subcutaneous,intramuscular or rectal administration, and oral administration ispreferred because it is simple. Although the administration dose isappropriately selected depending on the degree of the symptom of thepatient, type of the macrolide antibiotic and the like, the dose isusually about 300 to 500 mg in terms of the amount of the macrolideantibiotic per day per adult. The drug is effective at the dose employedfor the therapies of infectious diseases.

Adenomyosis of uterus is the state that the endometrium orendometrium-like tissue ectopically proliferates in myometrium, so thatit is a form of endometriosis and is included in endometriosis(“Surgical Pathology”, p. 713–715, published by Bunkodo; “ClinicalHistopathology”, p.661, published by Kyorin Shoin).

The present inventor intensively studied the findings of hysteromyoma.As a result, existence of mast cells and degranulation were observed.Thus, it was confirmed that the findings thereof are the same as theendometriosis from the observation of human cases. Therefore, macrolideantibiotics are effective for the therapy and prevention ofhysteromyoma, similarly to endometriosis.

As for the macrolide antibiotics used for the therapy and/or preventionof hysteromyoma, as well as the administration route and administrationdose, the above-described explanations for the endometriosis can beapplied as they are.

As for the formulation of the drug, any formulation methods ordinarilyemployed in the field of pharmaceuticals may be employed. For example,the macrolide antibiotic may be granulated together with an additivesuch as a polyoxyethylenesorbitan fatty acid ester, propylene glycol orsodium laurate, and the resultant may be made into tablets, but theformulation method is not restricted thereto. For example, a drug may beformulated by mixing 50 mg of clarithromycin and 34 mg ofpolyoxyethylenesorbitan fatty acid ester, granulating the resultingmixture and making tablets from the granulated mixture. Needless to say,the formulation method is not restricted thereto.

Since macrolide antibiotics have been used as therapeutic agents forvarious infectious diseases, safeties thereof to the extent demanded forpharmaceuticals have been confirmed.

The present invention will now be described more concretely by way ofexamples. However, the present invention is not limited to the followingexamples.

EXAMPLE 1 Therapeutic Effect for Endometriosis by Clarithromycin

Endometriosis model rats were prepared by the method described inMichael W. Vernon et al., FERTILITY AND STERILITY, Vol. 44, No. 5, Nov.1985. That is, endometriosis model rats were prepared as follows:Sprague-Dawley rats (female) of 8 weeks old were acclimatized for 2weeks under 12 hours light-dark condition. From each rat, right uterinehorn was excised under general anesthesia with sevoflurane and ketaminehydrochloride, and a tissue piece sizing 5 mm×5 mm was preparedtherefrom. The tissue piece was subjected to autotransplantation suchthat the endometrium surface is attached to peritoneum.

From 24 hours after the preparation of the endometriosis model rats,commercially available clarithromycin tablets (trademark “Clarith Tablet50 for Children” prepared by Taisho Pharmaceutical Co., Ltd) were orallyadministered to the rats for 3 days. The dose of administration was 10mg/kg per day in terms of clarithromycin. Clarithromycin was notadministered to control animals. Seven days after the preparation of themodel rats, at which the model lesion reached its peak, the peritoneumtissue including the graft up to the abdominal muscle was excised toobtain a lesion sample. From the thus obtained samples, light microscopespecimens (hematoxylin-eosin staining, toluidine blue staining) andelectron microscope specimens (uranium-lead double staining) wereprepared, and the existence of invaded mast cells, which is a symptom ofendometriosis, and the degree of interstitial proliferative lesion wereobserved.

As a result, in the control group, invasion of mast cells andinterstitial proliferative lesion were observed. In contrast, in theclarithromycin-administered group, invasion of mast cells was notobserved, and the degree of interstitial proliferative lesion wasapparently reduced.

EXAMPLE 2 Therapeutic Effect for Endometriosis by Roxithromycin

The same procedures as in Example 1 were repeated except thatroxithromycin (trademark “Rulid Tablet 150”, commercially available fromEisai Co., Ltd.) was used in place of clarithromycin. The administrationdose was 6 mg/kg per day in terms of roxithromycin. As a result, in thecontrol group, invasion of mast cells and interstitial proliferativelesion were observed. In contrast, in the roxithromycin-administeredgroup, invasion of mast cells was not observed, and the degree ofinterstitial proliferative lesion was apparently reduced.

EXAMPLE 3 Therapeutic Effect for Endometriosis by Azithromycin

The same procedures as in Example 1 were repeated except thatazithromycin (trademark “Zithromax Tablet 250 mg”, commerciallyavailable from Pfizer Pharmaceuticals Inc.) was used in place ofclarithromycin. The administration dose was 10 mg/kg per day in terms ofroxithromycin. As a result, in the control group, invasion of mast cellsand interstitial proliferative lesion were observed. In contrast, in theazithromycin-administered group, invasion of mast cells was notobserved, and the degree of interstitial proliferative lesion wasapparently reduced.

1. A method for therapy of endometriosis and/or hysteromyoma, comprisingadministering a macrolide antibiotic to a patient suffering fromendometriosis and/or hysteromyoma, in an amount effective for thetherapy of endometriosis and/or hysteromyoma.
 2. The method according toclaim 1, wherein said macrolide antibiotic is clarithromycin,roxithromycin or azithromycin.
 3. The method according to claim 1 or 2,wherein said macrolide antibiotic in an amount effective for the therapyof endometriosis is administered to a patient suffering fromendometriosis.